[Federal Register Volume 61, Number 87 (Friday, May 3, 1996)]
[Proposed Rules]
[Pages 20104-20115]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-11094]
[[Page 20103]]
_______________________________________________________________________
Part VIII
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Parts 210 and 211
Current Good Manufacturing Practice: Amendment of Certain Requirements
for Finished Pharmaceuticals; Proposed Rule
Federal Register / Vol. 61, No. 87 / Friday, May 3, 1996 / Proposed
Rules
[[Page 20104]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 210 and 211
[Docket No. 95N-0362]
RIN 0910-AA45
Current Good Manufacturing Practice; Proposed Amendment of
Certain Requirements for Finished Pharmaceuticals
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
certain requirements of the current good manufacturing practice (CGMP)
regulations for finished pharmaceuticals. These amendments would
clarify certain manufacturing, quality control, and documentation
requirements and would ensure that the regulations more accurately
encompass CGMP. In addition, the agency is updating the requirements
for process and methods validation to incorporate guidance previously
issued to industry and to reflect current practice. These proposed
amendments are intended to enhance the integrity of the drug
manufacturing process and the safety of drug products.
DATES: Submit written comments on the proposed rule by August 1, 1996.
Submit written comments on the information collection requirements by
June 3, 1996. FDA proposes that any final rule that may issue based
upon this proposal become effective 90 days after its date of
publication in the Federal Register.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857. Submit written comments on the information
collection requirements to the Office of Information and Regulatory
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., rm. 10235,
Washington, DC 20503.
FOR FURTHER INFORMATION CONTACT:
Thomas C. Kuchenberg, Center for Drug Evaluation and Research (HFD-
7), Food and Drug Administration, 7500 Standish Pl., Rockville, MD
20855, 301-594-1046; or
John M. Dietrick, Center for Drug Evaluation and Research (HFD-
325), Food and Drug Administration, 7500 Standish Pl., Rockville, MD
20855, 301-594-0098; or
William G. Marnane, Center for Veterinary Medicine (HFV-143), Food
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-
594-0678; or
Nancy Roscioli, Center for Biologics Evaluation and Research (HFM-
205), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD
20852-1448, 301-827-3031.
To obtain a copy of this document, contact the Division of
Congressional and Public Affairs (HFM-44), Center for Biologics
Evaluation and Research, Food and Drug Administration, 1401 Rockville
Pike, Rockville, MD 20852-1448. Send one self-addressed adhesive label
to assist that office in processing your requests.
The document may also be obtained by mail or FAX by calling the
Center for Biologics Evaluation and Research Voice Information System
at 1-800-835-4709.
Persons with access to the INTERNET may obtain the document in
several ways.
Users of ``Web Browser'' software, may obtain this document via the
World Wide Web by using the following Uniform Resource Locators
(URL's): http://www.fda.gov/cber/cberftp.html or ftp://ftp.fda.gov/
CBER/
The document may also be obtained via File Transfer Protocol (FTP).
Requesters should connect to the FDA FTP Server,
FTP.FDA.GOV(192.73.61.21). The Center for Biologics Evaluation and
Research (CBER) documents are maintained in a subdirectory called
``CBER'' on the server. Logins with the user name of anonymous are
permitted, and the user's e-mail address should be sent as the
password.
The ``READ.ME'' file in that subdirectory describes the available
documents which may be available as an ASCII text file (*.TXT), or a
WordPerfect 5.1 or 6.x document (*.w51,wp6), or both.
Finally, the document can be obtained by ``bounce-back e-mail''. A
message should be sent to: ``[email protected]''.
SUPPLEMENTARY INFORMATION:
I. History of the CGMP Regulations
On October 10, 1962, Congress enacted the Drug Amendments of 1962
(Pub. L. 87-781). The amendments include section 501(a)(2)(B) of the
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C.
351(a)(2)(B)), which deems a drug to be adulterated if:
* * * the methods used in, or the facilities or controls used
for, its manufacture, processing, packing, or holding do not conform
to or are not operated or administered in conformity with current
good manufacturing practice to assure that such drug meets the
requirements of this Act as to safety and has the identity and
strength, and meets the quality and purity characteristics, which it
purports or is represented to possess.
In the Federal Register of June 20, 1963 (28 FR 6385), FDA
published the first CGMP regulations (now codified as 21 CFR parts 210
through 226).
FDA has amended these regulations several times since 1963 to
ensure that they reflect the level of control necessary and that they
incorporate current technology to the extent that it influences
compliance with CGMP. Major revisions of the CGMP regulations were
issued in the Federal Registers of January 15, 1971 (36 FR 601),
September 29, 1978 (43 FR 45014), and January 20, 1995 (60 FR 4087).
The latter revision came about as the result of a comprehensive
assessment of the CGMP regulations, pursuant to the Regulatory
Flexibility Act (Pub. L. 96-354). During the assessment, the agency
solicited comments from the public with respect to any regulations that
might be perceived as being unnecessarily costly, burdensome, or
lacking public benefit. The revisions that became final in January 1995
were based on the comments that FDA received as well as the agency's
experience in applying those regulations.
II. Background of the Regulations
Since the development of the CGMP regulations, FDA has balanced the
need for precise, easily understood standards, which ease both
compliance and enforcement burdens, with the need to encourage
innovation and the development of improved manufacturing technologies.
The agency continues to balance such issues as part of the regulatory
process, and to choose the means of regulation most suited to any
particular aspect of the manufacturing process. The agency strives to
provide manufacturers with the discretion on how to achieve the level
of control necessary under CGMP, recognizing that in a few instances,
more direction from the agency is necessary because of the potential
for harm, the narrow range of acceptable means to accomplish a
particular CGMP objective, or to provide a uniform standard to the
entire industry. The CGMP regulations are based on fundamental concepts
of quality assurance: (1) Quality, safety, and effectiveness must be
designed and built
[[Page 20105]]
into a product; (2) quality cannot be inspected or tested into a
finished product; and (3) each step of the manufacturing process must
be controlled to maximize the likelihood that the finished product will
be acceptable (Ref. 1).
To accomplish these objectives, the agency must periodically
reassess and revise the CGMP regulations to accommodate advances in
technology that further safeguard the drug manufacturing process. As
technology and scientific knowledge evolve, so does understanding of
the critical material, equipment, and process variables that must be
defined and controlled to ensure end product homogeneity and conformity
with appropriate specifications. The CGMP regulations would not achieve
their statutorily mandated purposes if they were not periodically
reassessed to identify and eliminate obsolete provisions or to modify
provisions that no longer reflect the level of quality control that
current technology dictates and that the majority of manufacturers have
adopted.
Despite the agency's historic preference for a general regulatory
approach in the CGMP regulations, experience has shown that additional
specificity is warranted in certain areas. In addition, FDA regulatory
activities, and particularly its enforcement activities, have
demonstrated a need for greater uniformity in certain procedures to
protect the integrity of the drug product. When experience has
demonstrated that the acceptable choices with respect to any given
regulation are limited, FDA believes that the regulations will better
serve the public by reflecting the actual processes and procedures that
are acceptable to FDA. In those relatively few instances where such
specificity has been introduced into the regulations, FDA believes
industry will benefit by being able to focus its resources on
activities and processes that are known to be appropriate, rather than
on those that may eventually be found to be deficient.
FDA has determined that revisions to the CGMP regulations are
necessary at this time for a number of reasons. Rapid changes in
technology have created situations not anticipated when the CGMP
regulations were originally written or last revised. The agency's
enforcement and litigation experience has revealed persistent lack of
understanding among a limited number of manufacturers with respect to
certain of the CGMP regulations. Some pharmaceutical firms have not
subjected their procedures to sufficient scrutiny, while others have
failed to update such procedures to accommodate changes or advances in
the manufacturing process. In some cases, manufacturers may be relying
on methods and procedures that were acceptable at some time in the
past, but that are not acceptable in light of current standards.
In addition, FDA investigators have encountered serious validation
deficiencies at a number of firms. FDA is particularly concerned with
validation procedures designed to ensure the quality of the
manufacturing process. Enforcement and compliance actions have also
revealed a need for greater clarity and specificity in some portions of
the regulations.
These proposed revisions would, therefore, amend certain
requirements, define or redefine certain terms, and clarify industry
obligations with respect to several portions of the regulations. In
addition, the agency is proposing to revise certain laboratory control
and cross-contamination requirements and to clarify proper testing
procedures.
FDA believes that the procedures that would be required by this
proposal reflect practices already used by many manufacturers and
represent the prevailing industry standard. The agency emphasizes,
however, that for a given practice to be considered a current good
manufacturing practice (or promulgated as such in the regulations), it
is not a prerequisite that the practice actually be in use by a
majority, or a specific percentage of, the industry.
FDA has endeavored to ensure that the drug manufacturing process
will consistently produce products that are safe and have the quality
and purity which they purport to have, while recognizing the interests
of firms in retaining some discretion in achieving the level of control
necessary to comply with CGMP. FDA believes that the proposed rule
successfully addresses this balance; however, FDA invites comments
addressing specific proposals.
Other organizations have developed standards to define quality in
the manufacturing process. One such organization is the International
Organization of Standardization (ISO). The purpose of the ISO 9000
Standards is to provide generic guidance on quality in manufacturing
processes to both industry and vendors supplying industry. Five
standards (9000-9004) have been developed by the ISO Council and are
intended to be accepted worldwide. These standards are applicable to
any industry and are not specific to the pharmaceutical industry.
Compliance with the standards is voluntary. The principles and
practices elucidated in the ISO standards are not in conflict with
those provided by the CGMP regulations. Indeed, the voluntary ISO
standards share common principles with FDA's CGMP requirements.
III. Highlights of the Proposed Rule
The proposed rule would amend or revise a number of CGMP provisions
as follows:
A. Process Validation
The proposed rule would define ``process validation.'' Process
validation is a quality assurance function that helps to ensure drug
product quality by providing documented evidence that the manufacturing
process consistently does what it purports to do. Although process
validation is widely practiced by industry, FDA continues to find firms
that have never validated manufacturing processes for some finished
products.
Manufacturing process validation is a continuous undertaking
through which the process performance is constantly monitored and
evaluated. The complexities of modern manufacturing processes may make
it necessary to adapt or alter existing parameters while unexpected
variables may affect the manufacturing process and the finished
product. For example, a slight change in the physical characteristics
of an ingredient, or in the order of adding ingredients, may alter the
bioavailability of a drug product. In such a case, a sample of the
finished product could meet compendial dissolution criteria but present
a substantially different dissolution pattern than that produced before
changes were made. Because of such effects, revalidation may be
necessary after any change in process or product characteristics or
control procedures.
Although FDA has found numerous instances in which some firms have
failed to revalidate their processes for many years, the agency
recognizes that most of industry establishes and follows process
validation standards. Moreover, most in industry recognize the need for
revalidation (Ref. 2):
To preserve the validated status of a process, measures must be
taken that will allow any significant process changes to be
recognized and addressed promptly. Such change control measures can
apply to equipment, standard operating procedures, manufacturing
instructions, environmental conditions, or any other aspect of the
process system that has an effect on its state of control, and
therefore on the state of validation.
Accordingly, the agency is proposing to add new Sec. 211.220 to the
CGMP regulations specifying the nature and extent of validation that
are necessary to
[[Page 20106]]
ensure that the resulting products have the identity, strength,
quality, and purity characteristics that they purport to possess. The
proposed regulation also clarifies this requirement by using the term
``validation'' for those elements of the manufacturing process under
the control of the manufacturer, while the term ``verification'' is
used for those items produced by a person other than the manufacturer
or otherwise not under the control of the manufacturer.
FDA believes that the proposed rule reflects current industry
standards and processes that are implemented by many in the industry.
The proposed rule is necessary to: (1) Clarify the requirement to those
firms that have not implemented or properly conducted validation; (2)
ensure that all manufacturers are applying, and are evaluated against,
the same standard; and (3) clarify any remaining confusion about the
importance of validation in CGMP. FDA invites comments on whether this
proposal adequately achieves these goals in a manner consistent with
current industry practice.
B. Methods Validation
This proposed rule would also define in Sec. 210.3 ``methods
validation,'' which is the documented, successful evaluation of an
analytical method that provides a high level of assurance that such
method will consistently yield results that are accurate within
previously established specifications. The agency is proposing to move
the requirement for methods validation from Sec. 211.165(e) to
Sec. 211.222 for emphasis and to change the word ``established'' to
``validated'' for clarification. Current regulations require regulated
firms to validate all analytical methods that vary from compendial
methods. The suitability of a chosen method may be measured by such
analytical variables as precision, accuracy, limit of detection, limit
of quantitation, selectivity, range, linearity, and ruggedness. Methods
validation is intended to provide a high level of confidence that the
method selected is scientifically sound and that it serves its intended
analytical purpose.
Methods validation is central to ensuring the reliability of all
evidence that supports a product's identity, strength, quality, and
purity. For test results to be useful, significant, and reliable, the
methods used to analyze the data in such test results must also be
validated. In other words, a firm must establish that the analytical
methods it uses to assess or evaluate a manufacturing process
accurately measure variables affecting process control.
FDA recognizes that the scientific soundness of most of the methods
used by firms is well established. Compendial methods, for example,
reflect years of experience and evaluation and, in most cases, do not
need to be revalidated. In some instances, however, no generally
recognized analytical method exists or problems may develop with
existing methods. Product modification may also lead to innovative
analytical methods. FDA inspections have revealed that some firms use
methods that have become outdated, or claim to use analytical methods
that bear little relationship to those actually being used. In such
cases, new or revised analytical methods must be established as
scientifically sound and reproducible. FDA invites comments on this
proposal with respect to alternative means, if any, of assuring the
reliability of analytical methods.
C. Contamination
Drug products can become contaminated in a variety of ways. For
example, ineffective cleaning procedures may leave residues of the
product or cleaning agents in the equipment, production workers may
fail to take proper precautions while transporting a substance from one
area to another thereby introducing a contaminant to the second
production area, or particles may become airborne and travel to
production areas throughout the facility. Drug products may become
contaminated by a number of substances such as dust, dirt, debris,
toxic substances, infectious agents, or residue of other drugs or drug
components. Most contamination can be controlled to an acceptable level
through measures such as proper planning and implementation of cleaning
processes, employee training, gowning, and air filtration. Under CGMP,
a manufacturer will set contamination limits on a substance-by-
substance basis, according to both the potency of the substance and the
overall level of sensitivity to that substance.
However, controlling or reducing the likelihood of contamination is
inadequate when substances are present that may pose a serious risk to
humans or animals because their presence in even trace amounts may
render toxic an otherwise safe product. This is of particular concern
because a toxic reaction resulting from cross-contamination may not be
apparent to a health professional treating a patient suffering from
such a reaction, or may be impossible to trace to product
contamination. Penicillin, for example, is a substance that poses an
unacceptable risk of contamination because of the severe reaction some
humans have to it even at very low levels of exposure. Penicillin has
long been subject to specific CGMP regulations designed to reduce the
danger of cross-contamination. Because other substances, such as
cytotoxic agents or other antibiotics, pose at least as great a risk of
toxicity due to cross-contamination, FDA is proposing to expand the
contamination control requirements to encompass other sources of
contamination.
FDA has determined that substances posing a serious threat of
contamination, i.e., substances to which humans or animals show a
particular sensitivity even at extremely low levels, should be
controlled through dedicated production processes. For example,
dedicated facilities, air-handling equipment, and process equipment may
be necessary. The agency has refrained from establishing a list of
drugs or drug products that present such an unacceptable risk, because
such a list would quickly become obsolete. Moreover, the agency
believes that most manufacturers are knowledgeable about risks that are
associated with products that they produce, as well as with the
effective means to prevent cross-contamination. FDA stresses that
prevention of cross-contamination of potentially toxic substances is
the goal of this proposed rule. Because, in even small amounts, those
drugs may be toxic to humans or animals, FDA expects manufacturers to
identify any drugs that they produce that present the risk of cross-
contamination and to implement measures necessary to eliminate that
risk. FDA recognizes that, depending on the drug product, a variety of
measures may be acceptable to eliminate cross-contamination; there may,
however, be situations in which nothing short of dedicated facilities
or equipment will be sufficient. FDA invites comments on this proposal
especially with respect to any alternative means of addressing and
preventing cross-contamination.
D. Testing
FDA has concluded through its inspection and enforcement activities
that many manufacturers are not conducting adequate testing procedures
and are not adequately evaluating test discrepancies or investigating
failures. Such an investigation is crucial to ensure that the
manufacturing process is adequately controlled.
FDA recognizes the need to clarify the CGMP requirements in this
area so that all manufacturers are applying the same
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minimum standards and so that all manufacturers are thoroughly
assessing test results and discrepancies to ensure that all drug
products are safe and of the quality and purity which they purport to
be. This proposed rule would amend procedures for the testing of
components, calculation of yield, and blend testing. It would also
provide procedures for dealing with out-of-specification results. FDA
invites comments on alternate means of achieving adequate followup of
testing discrepancies or failures.
E. Quality Control
To further ensure that validation procedures are current, this
proposed rule would make the quality control unit responsible for
reviewing changes in product, process, equipment, or personnel, and for
determining if and when revalidation is required. The agency believes
that placing responsibility for oversight of validation procedures in
quality control units emphasizes the importance of proper validation to
quality control. This proposed rule stresses the importance of
validation by ensuring that a manufacturer will have a certain employee
or employees who are responsible for and accountable for ensuring that
the firm adequately evaluates its manufacturing process, validates the
processes and testing that must be validated, and thoroughly assesses
any discrepancies. FDA believes that this proposed regulation will
enhance compliance with CGMP through a means acceptable to most
manufacturers while providing FDA the ability to ensure accountability
and compliance.
IV. Description of the Proposed Rule
In general, the proposed rule would add new definitions to
Sec. 210.3 to clarify existing terms in the CGMP regulations and to
reflect proposed changes to the CGMP regulations for finished
pharmaceuticals. This proposal would also revise the CGMP regulations
for finished pharmaceuticals in part 211 to incorporate validation,
test, and documentation procedures necessary to protect the integrity
of the drug manufacturing process. Specific provisions are described in
more detail below.
A. Section 210.3--Definitions
Current Sec. 210.3(b) defines various terms that are used in the
CGMP regulations in parts 210 to 226.
This proposed rule would amend Sec. 210.3(b) to include new
definitions to clarify existing terminology and to define new terms
introduced in other provisions of this proposal. Under proposed
Sec. 210.3(b)(23), ``validation protocol'' would mean a written plan
describing the process to be validated, including production equipment
and how validation will be conducted. Such a plan would address
objective test parameters, product and process characteristics,
predetermined specifications, and factors which will determine
acceptable results.
Proposed Sec. 210.3(b)(24) would define ``process validation'' as
establishing, through documented evidence, a high degree of assurance
that a specific process will consistently produce a product that meets
its predetermined specifications and quality characteristics.
This proposal would define ``methods validation'' in
Sec. 210.3(b)(25) as establishing, through documented evidence, a high
degree of assurance that an analytical method will consistently yield
results that accurately reflect the quality characteristics of the
product tested.
Proposed Sec. 210.3(b)(26) would define ``equipment suitability''
as the established capacity of process equipment and ancillary systems
to operate consistently within established limits and tolerances.
Under proposed Sec. 210.3(b)(27), ``process suitability'' would
mean the established capacity of the manufacturing process to produce
effective and reproducible results consistently.-
Proposed Sec. 210.3(b)(28) would define ``out-of-specification'' as
an examination, measurement, or test result that does not comply with
preestablished criteria. This definition would be consistent with
Sec. 211.160(b), which requires laboratory controls for finished
pharmaceuticals to include the establishment of scientifically sound
and applicable specifications, standards, sampling plans, and test
procedures designed to ensure that components, drug product containers,
closures, in-process materials, labeling, and drug products conform to
appropriate standards of identity, strength, quality, and purity.
Proposed Sec. 210.3(b)(29) would define ``reprocessing'' as a
system of reworking batches that do not conform to standards or
specifications, including ``the steps taken to ensure that the
reprocessed batches will conform to all established standards,
specifications, and characteristics.'' Under the proposal,
``reprocessing'' would include a step or steps in the manufacturing
process that are out of the normal processing sequence or that are not
specifically provided for in the process.
Under proposed Sec. 210.3(b)(30), ``manufacturing process'' would
mean all manufacturing and storage steps in the creation of the
finished product from the weighing of components through the storing,
packaging, and labeling of the finished product, including, but not
limited to, the following: Mixing, granulating, milling, molding,
formulating, lyophilizing, tableting, encapsulating, coating,
sterilizing, and filling.
B. Section 211.22--Responsibilities of Quality Control Unit
Current Sec. 211.22 describes a quality control unit's
responsibilities. These responsibilities include ``the responsibility
and authority to approve or reject all components, drug product
containers, closures, in-process materials, packaging material,
labeling, and drug products'' as well as the authority to review
production records to determine whether errors have occurred. If errors
have occurred, Sec. 211.22 also gives quality control units the
authority to determine whether a firm has fully investigated the error.
The agency understands that some manufacturers would prefer that
the term ``quality control'' be replaced with ``quality assurance,''
that the functions of quality control and quality assurance be somehow
differentiated, or that a number of other terms be incorporated into
the regulation to reflect the distribution of quality oversight
responsibilities in various manufacturing settings.
FDA does not believe that such changes in terminology would be
useful. The difference between ``quality assurance'' and ``quality
control'' is recognized to be operational. The quality control unit is
usually responsible for performing the testing to assure that proper
specifications and limits are adhered to, while the quality assurance
unit is responsible for auditing methods, results, systems, and
processes, and for performing trend analyses. The functions described
in the proposed rule as the responsibility of the quality control unit
are designed to be implemented by all manufacturers, regardless of size
or organizational structure. However, such procedures can easily be
accommodated under organizational structures which utilize quality
assurance and quality control departments. The agency stated in the
preamble to the 1978 CGMP regulation and reiterates here, that the term
quality control ``unit'' is used in the regulations ``because it is a
term broadly applicable to any group within a manufacturing
establishment charged with the responsibility of quality control. The
[[Page 20108]]
Commissioner is not concerned about the name given by a firm to its own
unit that is responsible for quality control functions'' (43 FR 45014
at 45032).
Proposed 211.22(a) would require that firms be accountable with
respect to validation provisions and would give quality control units
the additional responsibility of reviewing and approving validation
protocols to assess their adequacy. Quality control units would also be
responsible for reviewing product, process, equipment, or other changes
to determine if and when revalidation is warranted. This change is
intended to make the quality control unit responsible for keeping
validation current and is a logical extension of the quality control
unit's role in ensuring product quality. The agency believes that, by
making clear such accountability, compliance with the validation
provisions will be more consistent and reliable.
C. Section 211.68--Automatic, Mechanical, and Electronic Equipment
Current Sec. 211.68(b) requires appropriate controls over computer
or related systems to ensure that only authorized personnel make
changes in master production and control records or other records. The
current regulation also requires that ``A backup file of data entered
into the computer or related system shall be maintained except where
certain data, such as calculations performed in connection with
laboratory analysis, are eliminated by computerization or other
automated processes.'' If computerization or other automated process
has eliminated such calculations, ``a written record of the program
shall be maintained along with appropriate validation data.''
Proposed Sec. 211.68(b) would replace the phrase ``appropriate
validation data'' with ``data establishing proper performance.'' This
change is intended to emphasize that the manufacturer must actually
establish proper performance.
D. Section 211.82--Receipt and Storage of Untested Components, Drug
Product Containers, and Closures
Section 211.82 governs the receipt and storage of untested
components, drug product containers, and closures. Section 211.82(b)
currently states, in part, that, ``Components, drug product containers,
and closures shall be stored under quarantine until they have been
tested or examined, as appropriate, and released.'' This provision is
designed to prevent the premature release of untested components,
containers, and closures that might be unsuitable for use in the
manufacturing process.
The proposal would remove the words, ``as appropriate,'' to
eliminate any ambiguity in the existing regulation. Although testing or
examination may vary with the particular component, drug product
container, or closure, the revision would also emphasize that it is, in
fact, accepted industry practice to conduct some testing or examination
before the components, drug product containers, or closures are
released from quarantine.
E. Section 211.84--Testing and Approval or Rejection of Components,
Drug Product Containers, and Closures
Section 211.84 pertains to the testing and approval or rejection of
components, drug product containers, and closures. Under current
Sec. 211.84(c)(1), containers of components ``shall be cleaned where
necessary, by appropriate means.''
This proposed rule would replace the phrases ``where necessary''
and ``by appropriate means'' with ``in a manner to prevent introduction
of contaminants into the raw material.'' This change will clarify that
the act of cleaning component containers is done for a particular
purpose, to prevent the introduction of contaminants, and that purpose
must, in all cases, be achieved.
FDA proposes to correct a typographical error in the text of
Sec. 211.84(c)(5) which requires that sample containers be identified
so that, among other things, the date on which the sample was taken can
be determined. The current regulation erroneously states ``the data on
which the sample was taken.'' FDA proposes to correct this by changing
``data'' to ``date.'' Additionally, proposed Sec. 211.84(d)(3) would
make two editorial changes by replacing the word ``conformance'' with
``conformity'' and ``procedure'' with ``specifications.''
F. Section 211.101--Charge-In of Components
Current Sec. 211.101 requires written production and control
procedures to assure that drug products have the identity, strength,
quality, and purity they purport or are represented to possess. Section
211.101(c) requires that weighing, measuring, or subdividing operations
be adequately supervised and that each container of component dispensed
to manufacturing be examined by a second person to ensure that: (1) The
component was released by the quality control unit; (2) the weight or
measure, as stated in batch production records, is correct; and (3) the
containers are properly identified.
The proposed rule would add a fourth requirement
(Sec. 211.101(c)(4)) that drug ingredients conform to the quality
specifications for the intended drug product. Active and inactive
ingredients come in varying grades and may not be interchangeable. This
proposal would require examination of the component by competent and
responsible individuals to ensure that the correct material is used.
This provision would provide additional assurance that the raw
materials used are appropriate for the intended batch, but is not
intended to require testing in addition to that required under subpart
E of part 211.
G. Section 211.103--Calculation of Yield
Section 211.100 currently requires maintenance of written
procedures for production and process controls to ensure that drug
products have the identity, strength, quality, and purity they purport
or are represented to possess. Section 211.103 currently requires that
actual yields and percentages of theoretical yield be determined at the
conclusion of appropriate phases of manufacturing, processing,
packaging, or holding of the drug product. These calculations are
performed by one person and independently verified by a second person.
Section 211.192 currently requires any unexplained discrepancy
(including a percentage of theoretical yield exceeding the maximum or
minimum percentages established in master production and control
records) to be thoroughly investigated.
This proposed rule would amend Sec. 211.103 to make clear that
there must be a written production and control procedure that will
require an investigation of any significant unexplained discrepancies
between actual yields and percentages of theoretical yield of the drug
product. This provision would help ensure that the source of any
potential problem is quickly and accurately identified and addressed.
H. Section 211.110--Sampling and Testing of In-Process Materials and
Drug Products
Current Sec. 211.110 establishes several requirements for the
sampling and testing of in-process materials and drug products. For
example, Sec. 211.110(a) requires written procedures for in-process
controls and tests or examinations to be conducted on appropriate
samples of in-process materials of each batch, whereas Sec. 211.110(b)
states that valid in-process specifications shall be consistent with
drug product final specifications and shall be derived from previous
acceptable process average and process
[[Page 20109]]
variability estimates where possible and determined by the application
of suitable statistical procedures. The regulation is designed to
protect the integrity of the manufacturing process and thus the safety
and efficacy of the drug product.
Sampling and testing techniques, however, are valid only insofar as
they provide a realistic representation of the material being sampled
or tested. Blend testing is important because it increases the
likelihood of quickly detecting uniformity problems that may produce
inferior batches. A large sample can mask differences that may be
significant in individual dosage units. Therefore, sample size must
approximate dosage size to provide an accurate representation of blend
uniformity. This proposal would create new Sec. 211.110(d) to help
ensure adequate testing. (The current paragraph (d) would be
redesignated as paragraph (e).) Proposed Sec. 211.110(d) would also
require that sampling be demonstrated through validation to be
representative of all portions of the blend.
This proposal would also require in new Sec. 211.110(f) that
validation of manufacturing processes be conducted in accordance with
process validation requirements in proposed Sec. 211.220. Validation of
these processes is intended, among other things, to ensure that the
sample is representative of all portions of the blend. For example,
firms sampling from drums containing the finished blend must
demonstrate that their sampling technique produces samples
representative of the entire batch.
I. Section 211.111--Time Limitations on Production
To assure the quality of the drug product, Sec. 211.111 currently
requires, when appropriate, time limits for the completion of each
phase of production.
This proposed rule would revise Sec. 211.111 to require for time-
sensitive procedures that manufacturers establish and validate maximum
time for completion of such procedures as part of the validation
required under Sec. 211.220. FDA expects that the validation of time-
sensitive procedures will be part of process validation.
J. Section 211.113--Control of Microbiological Contamination
Section 211.113(b) requires the establishment of, and adherence to,
written procedures designed to prevent microbiological contamination of
drug products purporting to be sterile. The provision also requires
that such procedures include ``validation of any sterilization
process.''
This proposed rule would amend Sec. 211.113(b) to refer to
validation of ``any sterilization or aseptic process.'' This change is
intended to reflect the fact that whether pharmaceutical firms use
aseptic processing techniques or whether they use terminal
sterilization, either technique must be validated.
K. Section 211.160--General Requirements
Currently, Sec. 211.160(b) requires that laboratory controls
include the establishment of scientifically sound and appropriate
specifications, standards, sampling plans, and test procedures designed
to ensure that components, drug product containers, closures, in-
process materials, labeling, and drug products conform to appropriate
standards of identity, strength, quality, and purity.
This proposal would specify a requirement for the establishment of
scientifically sound resampling, retesting, and data interpretation
procedures.
Currently under Sec. 211.160(b)(1), laboratory controls shall
include a determination of conformance to appropriate written
specifications for the acceptance of each lot within each shipment of
components, drug product containers, closures, and labeling used in the
manufacture, processing, packing, or holding of drug products.
This proposal would make editorial changes, replacing
``conformance'' with ``conformity'' and ``appropriate'' with
``applicable.''
L. Section 211.165--Testing and Release for Distribution
Section 211.165(e) requires that the accuracy, sensitivity,
specificity, and reproducibility of test methods used by a firm be
established and documented. Because other revisions in this proposal
would clarify and set forth this requirement, the proposal would remove
Sec. 211.165(e) and redesignate paragraph (f) as paragraph (e).
M. Section 211.166--Stability Testing
Currently, Sec. 211.166 requires a written stability testing
program and provides the elements of such a program. The current
provision requires that an adequate number of batches be tested to
determine an appropriate expiration date. This proposal would
redesignate current Sec. 211.166(c) and (d) as Sec. 211.166(d) and (e),
and add new Sec. 211.166(c) to require placing at least one additional
batch into the stability testing program each year.
For some time, requirements for new drug and abbreviated new drug
applications and biological products applications have included as a
condition for approval a commitment to place the initial three
production batches and at least one additional batch annually into the
stability testing program. It is necessary to place the three initial
batches in the stability testing program to account for batch
variability and to confirm the previously established expiration date.
There are, however, variations in the production process during the
lifetime of a drug product such as changes in personnel, raw materials
and suppliers, manufacturing environment, and equipment. Because a
dosage form is typically a complex unit, such changes may have an
impact on drug product stability. Because of this, the agency believes
it is imperative that ongoing production be periodically monitored to
ensure the stability of the product. The agency believes, further, that
the necessity for continued stability testing is recognized by the
industry and is now standard industry practice. The agency invites
comments on this proposed provision.
N. Section 211.180--General Requirements
Section 211.180(a) requires the retention of production, control,
or distribution records specifically associated with a batch of a drug
product, for at least 1 year after the expiration date of the batch.
FDA believes that validation records, including the validation
protocol, production and control records, data, and the study report,
should not be discarded after the validation batches expire. They
should be retained for as long as the validated process is used and as
long as any batches made by the validated process may be available to
consumers. The proposal would therefore amend this section to add a
requirement that the validation records required by proposed new
Sec. 211.220 also be retained for at least 1 year after the expiration
date of all batches associated with that validated process.
O. Section 211.192--Production Record Review
FDA's experience has revealed a variety of written and unwritten
practices and procedures under which firms have disregarded out-of-
specification laboratory results, after minimal retesting, resampling,
inappropriate averaging of results, or inappropriate outlier testing.
Some firms then proceeded to release a product without a thorough
investigation or an adequate justification for disregarding an out-of-
specification result.
[[Page 20110]]
Out-of-specification results can be caused by laboratory error,
nonprocess or operator error, or by process-related error. The agency
recognizes that laboratory errors occur and that a thorough
investigation, supported by evidence and documentation, may, for
instance, indicate an out-of-specification result caused by laboratory
personnel errors or equipment failures. However, unless and until an
investigation indicates that this is the case and the investigation is
completed and documented, FDA believes that the out-of-specification
result should not be discarded or disregarded. Moreover, FDA emphasizes
that, although retesting may be an appropriate part of an
investigation, an investigation consisting solely of repeated retesting
is clearly inadequate. If quality is not built into a drug product,
retesting cannot make it conform to specifications.
FDA recognizes the distinction between the limited investigation
that may be necessary to identify a laboratory error and the more
extensive investigation and testing necessary when out-of-specification
results may be attributed to another cause. The agency also recognizes
that the industry may impose additional criteria beyond those required
to ensure identity, strength, quality, and purity under CGMP
regulations or as required by a drug application. The agency encourages
such internal controls. Under such circumstances, a manufacturer could
have test results that violate internal standards although they would
not be out-of-specification, as defined in these regulations.
FDA believes, however, that CGMP requires written procedures to be
in place to determine the cause of any apparent failure, discrepancy,
or out-of-specification result. If the out-of-specification result
cannot be clearly attributed to laboratory error, then the quality
control unit should ensure that a thorough investigation is conducted
and supported by a written record. Certain elements and procedures are
crucial to a systematic and orderly investigation. Consequently, this
proposed rule would revise the section heading of Sec. 211.192 to read
``Production, control, and laboratory record review and investigation
of discrepancies,'' and would amend Sec. 211.192(b) to require written
procedures including the following: (1) Procedures for attempting to
identify the cause of the failure or discrepancy; (2) criteria for
determining whether out-of-specification results were caused by
sampling or laboratory error; (3) scientifically sound procedures and
criteria for the exclusion of any test data found to be invalid due to
laboratory or sampling error; (4) scientifically sound procedures and
criteria for additional sampling and testing, if necessary, during the
investigation; (5) procedures and criteria for extending the
investigation to other batches or other products; (6) procedures for
review and evaluation of the investigation, including all test results,
by the quality control unit, to ensure a thorough investigation; and
(7) criteria for final approval or rejection of the batch involved, and
for taking action on other batches and products if indicated by the
investigation.
The number of retests performed before a firm concludes that an
unexplained out-of-specification laboratory result is invalid, or that
a product is unacceptable, is a matter of scientific judgment. FDA does
not intend to issue regulations on specific retesting procedures.
Rather, the proposed rule would require each firm to have written
investigation and retesting procedures, applying scientifically sound
criteria, that limit the amount of retesting permitted and indicate the
point at which testing ends and the product is evaluated.
Proposed Sec. 211.192(c) would require written records of the
investigation to be made and shall include: (1) The reason for the
investigation; (2) a description of the investigation made, including
all laboratory tests; (3) the results of the investigation including
all laboratory test results involved in the investigation; (4)
scientifically sound and appropriate justification for excluding any
out-of-specification laboratory result found to be invalid; (5) if
laboratory results are found to be invalid, the subsequent laboratory
results supporting the final determination of the tested item's
conformity to appropriate specifications for acceptance; (6) the
conclusions and subsequent actions concerning all batches and products
that may have been associated with the failure or discrepancy; (7) the
signature(s) and date(s) of the person(s) responsible for approving the
record of the investigation; and (8) the signature(s) and date(s) of
the person(s) responsible for the final decision on disposition of the
batch, and on other batches and products involved. The agency
specifically invites comments on these proposed requirements.
P. Section 211.220--Process Validation, and Section 211.222--Methods
Validation
FDA proposes to add new subpart L to part 211 entitled
``Validation.'' The new subpart would consist of two regulations:
Sec. 211.220 for ``process validation'' (establishing through
documented evidence a high degree of assurance that a specific process
will consistently produce a product that meets predetermined
specifications and quality characteristics), and Sec. 211.222 for
``methods validation'' (establishing through documented evidence a high
degree of assurance that an analytical method will consistently yield
results that accurately reflect the quality characteristics of the
material tested).
These proposed regulations are intended to clarify the requirements
for validation and to provide the basic elements of an acceptable
validation procedure. FDA believes, in general, that scientific
knowledge and industry experience have defined the basic elements of a
sound validation system. Validation has proven to be an effective
technique for protecting the integrity of the drug manufacturing
process.
Although the particular requirements of process validation will
vary according to such factors as the nature of the drug product (e.g.,
sterile versus nonsterile) and the complexity of the process, the
requirements of the proposed subpart are generally applicable to all
drug products and provide a foundation for building a comprehensive
approach to process validation.
Proposed Sec. 211.220(a) would require validation of all drug
manufacturing processes including, but not limited to, computerized
systems involved in the manufacturing process. Under the proposal, the
manufacturing process would include all manufacturing steps in the
creation of the finished product, including, but not limited to,
cleaning, weighing, measuring, mixing, blending, compressing, filling,
packaging, and labeling. Time-sensitive steps in the manufacturing
process would be validated. Such validation ensures that the impact of
any interruption in the manufacturing process on drug product safety
and efficacy is fully understood by the manufacturer.
Proposed Sec. 211.220(b) would establish requirements for a
validation protocol. The validation protocol is the blueprint of the
validation process for a particular drug product. The protocol would
specify a sufficient number of replicate process runs to demonstrate
reproducibility and provide an accurate measure of variability among
successive runs. Validation documentation would include evidence of the
suitability of materials and the proper performance and reliability of
the equipment and systems used to manufacture a drug product. The
execution of the protocol and the test results would be
[[Page 20111]]
documented and the manufacturer would be required to retain such
documentation.
Proposed Sec. 211.220 would require that equipment and processes be
designed and selected to be consistently capable of achieving product
specifications. Determining equipment suitability would include testing
to verify whether the equipment is capable of performing adequately
within the operating limits of the process. A determination of process
suitability would include rigorous testing and documentation to
demonstrate that the process is both effective and reproducible. A
manufacturer should test those parts of the process that may affect
product quality or may cause variability.
Proposed Sec. 211.220(d) would require a quality assurance system
to implement revalidation procedures whenever there are changes,
including reprocessing, that could affect product effectiveness or
product characteristics, or whenever changes are observed in product
characteristics.
Proposed Sec. 211.222, ``methods validation,'' would require the
manufacturer to establish and document the accuracy, sensitivity,
specificity, reproducibility, and any other attribute necessary to
validate test methods. The validation would be required to meet the
existing requirements for laboratory records provided at
Sec. 211.194(a)(2). These requirements include a ``statement of each
method used in the testing of the sample,'' indicating the location of
the data that establish that the methods used in testing the sample
meet proper standards of accuracy and reliability as applied to the
tested product. The proposed provision is designed to ensure that
testing methods used are relevant to product quality and the integrity
of the manufacturing process. FDA invites comments on this proposal,
especially on alternative means, if any, of assuring the reliability of
manufacturing processes and analytical methods.
Q. Section 211.240--Control of Chemical and Physical Contaminants
FDA's experience indicates that the potential dangers of
contamination are more extensive and varied than once believed; for
example, high potency drugs, such as penicillin, cephalosporins, and
cytotoxic anticancer agents, may pose health risks even at low levels
of exposure. Cross-contamination may result in the adulteration of
other drugs, and even minimal amounts could have serious adverse
effects on persons who are allergic to the contaminant. Moreover,
because the identity or even the presence of the contaminant may be
unknown, health care professionals providing care to a patient
suffering from such an adverse effect may be unable to provide
appropriate medical intervention.
FDA is thus proposing to add new subpart M, which would be directed
to the control of chemical and physical contaminants. The new subpart,
consisting of proposed Sec. 211.240, would require firms to anticipate
and prevent specific contamination problems, including, but not limited
to, those presented by penicillin. As a result, FDA is also proposing
to remove Secs. 211.42(d) and 211.176 regarding separate facilities for
manufacturing penicillin and penicillin contamination and to
incorporate their requirements in Sec. 211.240.
Proposed Sec. 211.240(a) would require the implementation of
written procedures designed to prevent objectionable chemical and
physical contamination, including cross-contamination. Section
211.240(b) would require dedicated production, which may include
facilities, air handling, or process equipment, in those circumstances
in which contaminants pose a special danger to human or animal health.
Such contaminants include, but are not limited to, penicillin,
cephalosporins, cytotoxic anti-cancer agents, and infectious agents
(e.g., spore-bearing organisms and live viruses). Dedicated production
would also be required under proposed Sec. 211.240(b) if there are no
reasonable methods for the cleaning and removal of a drug substance or
compound residues from buildings, facilities, and equipment.
If there is a reasonable possibility that a drug has been exposed
to cross-contamination, proposed Sec. 211.240(c) would require that the
product be tested for the potential contaminant. It would also require
the establishment of limits for potential contaminants, and prohibit
the release of a product for distribution if these limits are exceeded.
The proposed contamination provisions are designed to accommodate
technological changes. For example, under the proposed rule, a
manufacturer might develop a drug product of high therapeutic potential
that also poses a high risk of contamination. If this hypothetical drug
product contamination posed a special danger to human health, dedicated
facilities would be required. If, however, experience demonstrated that
the drug product did not pose such a risk, or if changes in
manufacturing technology greatly reduced the risk, dedicated facilities
might no longer be required.
V. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
VI. Paperwork Reduction Act of 1995
This proposed rule contains information collections which are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (Pub. L. 104-13). The title,
description, and respondent description of the information collection
are shown below with an estimate of the annual reporting and
recordkeeping burden. Included in the estimate is the time for
reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing the
collection of information.
Title: Current Good Manufacturing Practice; Proposed Amendment of
Certain Requirements for Finished Pharmaceuticals.
Description: FDA is proposing to amend its CGMP regulations to
establish procedures and specifications for testing, sampling, and
other quality control activities; to establish criteria for initiating
and performing out-of-specification investigations; and to control
chemical and physical contaminants. These amendments would clarify
certain manufacturing, quality control, and documentation requirements
and ensure that the regulations more accurately encompass CGMP. In
addition, the agency is updating the requirements for process and
methods validation to incorporate guidance previously issued to
industry and to reflect current practice. These proposed changes are
intended to enhance the integrity of the drug manufacturing process and
the safety of drug products. The total recordkeeping requirements are
estimated at 89,884 hours, as a one-time reporting burden.
Description of Respondents: Businesses or other for profit and
small businesses or organizations.
[[Page 20112]]
----------------------------------------------------------------------------------------------------------------
Estimated Reporting Burden \1\
-----------------------------------------------------------------------------------------------------------------
Number of Responses per Total Annual Hours Per
CFR Section Respondents Respondent Responses Response Total Hours
----------------------------------------------------------------------------------------------------------------
211.160(b) and
(b)(1) 1,077 1 1 8.2 8,871
211.192(a) 4,184 1 1 6.7 28,060
211.192(b) 4,184 1 1 9.6 40,156
211.240 2,205 1 1 6.3 12,797
Total 89,884
----------------------------------------------------------------------------------------------------------------
\1\ Because some of the numbers underlying these estimates have been rounded, figures in this table are
approximate. There are no maintenance and operation costs nor start up and capital costs. The chart represents
a one time burden.
As required by section 3507(d) of the Paperwork Reduction Act of
1995, FDA has submitted a copy of this proposed rule to OMB for its
review of these previously approved information collection
requirements. The agency solicits comments on the information
collection requirements in order to: (1) Evaluate whether the proposed
collection of information is necessary for the proper performance of
the functions of the agency, including whether the information will
have practical utility; (2) evaluate the accuracy of the agency's
estimate of the burden of the proposed collection of information,
including the validity of the methodology and assumptions used; (3)
enhance the quality, utility, and clarity of the information to be
collected; and (4) minimize the burden of the collection of information
on those who are to respond, including through the use of appropriate
automated, electronic, mechanical, or other technological collection
techniques or other forms of information technology, e.g., permitting
electronic submission of responses. Organizations and individuals
desiring to submit comments on the information collection requirements
should direct them to the Office of Information and Regulatory Affairs,
OMB, New Executive Office Bldg., rm. 10235, 725 17th St. NW.,
Washington, DC 20503, Attention: Desk Officer for FDA.
VII. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. The detailed data for the
cost analysis were developed by Eastern Research Group, Inc., under
contract to FDA, and their full report is on file at the Dockets
Management Branch (address above).
The proposed changes to the CGMP regulations will affect
manufacturers of finished human and veterinary pharmaceuticals,
including medical gases, and repackers and relabelers of drug products.
The majority of the proposed changes clarify existing manufacturing,
quality control, and documentation requirements and represent current
industry practice for the majority of firms. As such, they will have
little or no economic impact on the majority of the industry. Some
firms are not, however, operating in conformance with CGMP and the
estimates represent the agency's best assessment of the incremental
increase in costs that these firms would incur in implementing full
compliance with the proposed changes.
The total cost is estimated to be a one-time expenditure of
$2,900,000 ($0.7 million annualized over 5 years at a 7 percent
discount rate). These costs would be generated by proposed changes that
would require some manufacturers to revise existing, or develop new,
standard operating procedures.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact on small
entities. Because this regulation will not impose significant new costs
on a large number of drug manufacturing operations, the agency
certifies that the proposed rule will not have a significant economic
impact on a substantial number of small entities. The agency estimates
that, to comply with the proposal, establishments will incur additional
annualized costs ranging from approximately $60 to $450 for
establishments with fewer than 100 employees and from approximately
$175 to $600 for establishments with 250 or more employees. For
individual establishments, the impact of the proposal will depend on
numerous factors, such as the type of establishment, the level of
current conformance with the proposed changes, and the number and
nature of products produced. Provisions of this proposal represent the
most cost-effective option evaluated. Several of the rejected
alternatives considered (such as revisions to Sec. 211.84(d)(2) and
(d)(3)) would have increased total costs by $14 to $27 million.
As a result of its analysis, FDA has determined that the proposed
revision to the CGMP regulations for human and veterinary
pharmaceuticals is not a significant regulatory action as defined by
Executive Order 12866, and that the proposal will not have a
significant economic impact on a substantial number of small entities.
Therefore, under the Regulatory Flexibility Act, no further analysis is
required.
VIII. Effective Date
FDA proposes that any final rule that may issue based on this
proposal become effective 90 days after the date of its publication in
the Federal Register.
IX. Request For Comments
Interested persons may, on or before August 1, 1996, submit to the
Dockets Management Branch (address above) written comments regarding
this proposal. Two copies of any comments are to be submitted except
that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document. Received comments may be seen in the office above between 9
a. m. and 4 p.m., Monday through Friday.
X. References
The following references, which have been consulted in the drafting
of this proposed rule, are readily and publicly available in a variety
of locations. They have also been placed on display in the Dockets
Management Branch (address
[[Page 20113]]
above) and may be seen by interested persons between 9 a.m. and 4 p.m.,
Monday through Friday.
1. Juran, Quality Control Handbook, 4th ed., McGraw-Hill, 1988.
2. Pharmaceutical Manufacturers Association's (now known as
Pharmaceutical Research and Manufacturers of America) Validation
Advisory Committee, ``Process validation concepts for drug
products,'' Pharmaceutical Technology, September 1985, p. 82.
List of Subjects
21 CFR Part 210-
Drugs, Packaging and containers.
21 CFR Part 211
Drugs, Labeling, Laboratories, Packaging and containers,
Prescription drugs, Reporting and recordkeeping requirements,
Warehouses.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 210 and 211 be amended as follows.
PART 210--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING,
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL
1. The authority citation for 21 CFR part 210 continues to read as
follows:
Authority: Secs. 201, 501, 502, 505, 506, 507, 512, 701, 704 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,
355, 356, 357, 360b, 371, 374).
2. Section 210.3 is amended by adding new paragraphs (b)(23)
through (b)(30) to read as follows:
Sec. 210.3 Definitions.
* * * * *
(b) * * *
(23) Validation protocol means a written plan describing the
process to be validated, including production equipment, and how
validation will be conducted, including objective test parameters,
product and/or process characteristics, predetermined specifications,
and factors which will determine acceptable results.
(24) Process validation means establishing, through documented
evidence, a high degree of assurance that a specific process will
consistently produce a product that meets its predetermined
specifications and quality characteristics.
(25) Methods validation means establishing, through documented
evidence, a high degree of assurance that an analytical method will
consistently yield results that accurately reflect the quality
characteristics of the product tested.
(26) Equipment suitability is the established capacity of process
equipment and ancillary systems to operate consistently within
established limits and tolerances.
(27) Process suitability is the established capacity of the
manufacturing process to produce effective and reproducible results
consistently.
(28) Out-of-specification means an examination, measurement, or
test result that does not comply with preestablished criteria, as
required by Sec. 211.160(b) of this chapter.
(29) Reprocessing is a system of reworking batches that do not
conform to standards or specifications. It includes the steps taken to
ensure that the reprocessed batches will conform to all established
standards, specifications, and characteristics. It includes a step or
steps in the manufacturing process that are out of the normal
processing sequence or that are not specifically provided for in the
process.
(30) Manufacturing process means manufacturing and storage steps in
the creation of the finished product from the weighing of components
through the storing, packaging, and labeling of the finished product.
Such steps include, but are not limited to, the following: Mixing,
granulating, milling, molding, formulating, lyophilizing, tableting,
encapsulating, coating, sterilizing, and filling.
PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS
3. The authority citation for 21 CFR part 211 continues to read as
follows:
Authority: Secs. 201, 501, 502, 505, 506, 507, 512, 701, 704 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,
355, 356, 357, 360b, 371, 374).
4. Section 211.22 is amended by adding a sentence at the end of
paragraph (a) to read as follows:
Sec. 211.22 Responsibilities of quality control unit.
(a) * * * The quality control unit shall be responsible for the
review and approval of validation protocols and for the review of
changes in product, process, equipment, or other changes to determine
if and when revalidation is warranted.
* * * * *
Sec. 211.42 [Amended]
5. Section 211.42 Design and construction features is amended by
removing paragraph (d).-
6. Section 211.68 is amended by revising the fifth sentence in
paragraph (b) to read as follows:
Sec. 211.68 Automatic, mechanical, and electronic equipment.
* * * * *
(b) * * * In such instances, a written record of the program shall
be maintained along with data establishing proper performance. * * *
7. Section 211.82 is amended by revising the first sentence in
paragraph (b) to read as follows:
Sec. 211.82 Receipt and storage of untested components, drug product
containers, and closures.
* * * * *
(b) Components, drug product containers, and closures shall be
stored under quarantine until they have been tested or examined and
released. * * *
8. Section 211.84 is amended by revising paragraph (c)(1), by
removing in paragraph (c)(5) the word ``data'' and adding in its place
the word ``date'', and by removing in the first sentence of paragraph
(d)(3) the word ``conformance'' and adding in its place the word
``conformity'' and removing the word ``procedures'' and adding in its
place the word ``specifications'' to read as follows:
Sec. 211.84 Testing and approval or rejection of components, drug
product containers, and closures.
* * * * *
(c) * * *
(1) The containers of components selected shall be cleaned in a
manner to prevent introduction of contaminants into the raw material.
* * * * *
9. Section 211.101 is amended by revising paragraph (c)(3) and by
adding new paragraph (c)(4) to read as follows:
Sec. 211.101 Charge-in of components.
* * * * *
(c) * * *
(3) The containers are properly identified; and
(4) The components conform to the quality specifications for the
intended drug product.
* * * * *
10. Section 211.103 is amended by adding a new sentence to the end
of the paragraph to read as follows:
Sec. 211.103 Calculation of yield.
* * * There shall also be a written production and control
procedure for investigating any discrepancies in yield outside the
maximum or minimum percentages established in master production and
control records.
[[Page 20114]]
11. Section 211.110 is amended by redesignating paragraph (d) as
paragraph (e) and by adding new paragraphs (d) and (f) to read as
follows:
Sec. 211.110 Sampling and testing of in-process materials and drug -
products.
* * * * *
(d) When blend uniformity testing is needed to determine blend
homogeneity, the sample size in both validation and ordinary production
batches should approximate the dosage size. Sampling shall be
demonstrated through validation to be representative of all portions of
the blend.
* * * * *
(f) Validation of manufacturing processes required by this section
shall be conducted in accordance with Sec. 211.220.
12. Section 211.111 is amended by revising the first sentence to
read as follows:
Sec. 211.111 Time limitations on production.
When appropriate, the manufacturer shall establish and validate
maximum time limits for each phase of production as part of validation
procedures required under Sec. 211.220. * * *
13. Section 211.113 is amended by revising the last sentence in
paragraph (b) to read as follows:
Sec. 211.113 Control of microbiological contamination.
* * * * *
(b)-* * * Such procedures shall include validation of any
sterilization or aseptic process.
14. Section 211.160 is amended by revising the first sentence in
the introductory text of paragraph (b) and the first sentence in
paragraph (b)(1) to read as follows:
Sec. 211.160 General requirements.
* * * * *
(b) Laboratory control shall include the establishment of
scientifically sound and applicable written specifications, standards,
sampling plans, and test procedures including resampling, retesting,
and data interpretation procedures designed to ensure that components,
drug product containers, closures, in-process materials, labeling, and
drug products conform to appropriate standards of identity, strength,
quality, and purity. * * *
(1) Determination of conformity to applicable written
specifications for the acceptance of each lot within each shipment of
components, drug product containers, closures, and labeling used in the
manufacture, processing, packing, or holding of drug products. * * *-
* * * * *
Sec. 211.165 [Amended]
15. Section 211.165 Testing and release for distribution is amended
by removing paragraph (e) and redesignating paragraph (f) as paragraph
(e).
16. Section 211.166 is amended by redesignating paragraphs (c) and
(d) as paragraphs (d) and (e), respectively, and by adding new
paragraph (c) to read as follows:
Sec. 211.166 Stability testing.
* * * * *
(c) After the expiration date has been determined, there shall be
an ongoing testing program for each drug product to ensure product
stability. At least one batch of each drug product shall be added to
the stability program annually.
* * * * *
Sec. 211.176 [Removed]
17. Section 211.176 Penicillin contamination is removed.
18. Section 211.180 is amended by revising paragraph (a) to read as
follows:
Sec. 211.180 General requirements.
(a) Any production, control, validation, or distribution record
that is required to be maintained in compliance with this part and is
specifically associated with a batch of a drug product shall be
retained for at least 1 year after the expiration date of the last
batch produced with that validated process or, in the case of certain
OTC drug products lacking expiration dating because they meet the
criteria for exemption under Sec. 211.137, 3 years after distribution
of the batch.
* * * * *
19. Section 211.192 is revised to read as follows:
Sec. 211.192 Production, control, and laboratory record review and -
investigation of discrepancies.
(a) Written procedures shall be established and followed requiring
the review and approval by the quality control unit of all drug product
production, control, and laboratory records, including packaging and
labeling, to determine compliance with all established and approved
written procedures and specifications before a batch is released or
distributed.
(b) Written procedures shall be established and followed requiring
the thorough investigation of any unexplained discrepancy (including a
percentage of theoretical yield exceeding the maximum or minimum
percentages established in master production and control records) or
the failure of a batch or any of its components or in-process materials
to meet any of its specifications (including any out-of-specification
test result), whether or not the batch has already been distributed.
The investigation shall extend to other batches of the same drug
product and other drug products that may have been associated with the
specific failure or discrepancy. Such procedures shall include:
(1) Procedures for attempting to identify the cause of the failure
or discrepancy.
(2) Criteria for determining whether out-of-specification results
were caused by sampling or laboratory error.
(3) Scientifically sound procedures and criteria for the exclusion
of any test data found to be invalid due to laboratory or sampling
error.
(4) Scientifically sound procedures and criteria for additional
sampling and testing, if necessary, during the investigation.
(5) Procedures and criteria for extending the investigation to
other batches or other products.
(6) Procedures for review and evaluation of the investigation,
including all test results, by the quality control unit, to ensure a
thorough investigation.
(7) Criteria for final approval or rejection of the batch involved,
and for taking action on other batches and products if indicated by the
investigation.
(c) A written record of the investigation shall be made and shall
include:
(1) The reason for the investigation.
(2) A description of the investigation made, including all
laboratory tests.
(3) The results of the investigation, including all laboratory test
results involved in the investigation.
(4) Scientifically sound and appropriate justification for
excluding any out-of-specification laboratory result found to be
invalid.
(5) If laboratory results are found to be invalid, the subsequent
laboratory results supporting the final determination of the tested
item's conformity to all appropriate specifications for acceptance.
(6) The conclusions and subsequent actions concerning all batches
and products that may have been associated with the failure or
discrepancy.
(7) The signature(s) and date(s) of the person(s) responsible for
approving the record of the investigation.
(8) The signature(s) and date(s) of the person(s) responsible for
the final decision on disposition of the batch, and on other batches
and products involved.
20. New subpart L, consisting of Secs. 211.220 and 211.222, is
added to read as follows:
[[Page 20115]]
Subpart L--Validation
Sec.
211.220 Process validation.
211.222 Methods validation.
Subpart L--Validation
Sec. 211.220 Process validation.
(a) The manufacturer shall validate all drug product manufacturing
processes including, but not limited to, computerized systems that
monitor and/or control the manufacturing process. The manufacturing
process includes all manufacturing steps in the creation of the
finished product including, but not limited to, the following
procedures: Cleaning, weighing, measuring, mixing, blending,
compressing, filling, packaging, and labeling.
(b) Validation protocols that identify the product and product
specifications and specify the procedures and acceptance criteria for
the tests to be conducted and the data to be collected during process
validation shall be developed and approved. The protocol shall specify
a sufficient number of replicate process runs to demonstrate
reproducibility of the process and provide an accurate measure of
variability among successive runs. Validation documentation shall
include evidence of the suitability of materials and the performance
and reliability of equipment and systems. The manufacturer shall
document execution of the protocol and test results.
(c) The manufacturer shall design or select equipment and processes
to ensure that product specifications are consistently achieved. The
manufacturer's determination of equipment suitability shall include
testing to verify that the equipment is capable of operating
satisfactorily within the operating limits required by the process.
Process suitability shall include documented rigorous testing to
demonstrate the effectiveness and reproducibility of the process. Parts
of the process that may cause variability or otherwise affect product
quality shall be tested.
(d) There shall be a quality assurance system in place which
requires revalidation whenever there are changes in packaging,
component characteristics, formulation, equipment, or processes,
including reprocessing, that could affect product effectiveness or
product characteristics, and whenever changes are observed in product
characteristics.
Sec. 211.222 Methods validation.
The accuracy, sensitivity, specificity, and reproducibility of test
methods used by a manufacturer shall be validated and documented. Such
validation and documentation shall be accomplished in accordance with
Sec. 211.194(a)(2).
21. New subpart M, consisting of Sec. 211.240, is added to read as
follows:
Subpart M--Contamination
Sec.
211.240 Control of chemical and physical contaminants.
Subpart M--Contamination
211.240 Control of chemical and physical contaminants.
(a) The manufacturer shall implement written procedures designed to
prevent objectionable chemical and physical contamination, including
cross-contamination.
(b) Dedicated production, which may include facilities, air
handling equipment, and/or process equipment, shall be employed where
contaminants, such as penicillin, pose a special danger to human or
animal health or if there are no reasonable methods for the cleaning
and removal of drug substances and/or component residues from
buildings, facilities, and equipment.
(c) If a reasonable possibility exists that a drug has been exposed
to cross-contamination, the manufacturer shall test the product for the
presence of the potential contaminant. The manufacturer shall establish
appropriate limits for such potential contaminants. Products that
exceed the established limits shall not be released for distribution.
Dated: March 29, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-11094 Filed 5-2-96; 8:45 am]
BILLING CODE 4160-01-F
